1. Field of the Invention
The present invention relates to novel 2,3-dihydro-iminoisoindole derivatives that are useful as pharmaceuticals, to their pharmacologically acceptable salts, and to therapeutic or prophylactic agents for diseases associated with thrombus formation that contain the foregoing as active ingredients.
2. Related Background Art
Living organisms with damaged blood vessels avoid hemorrhage death by rapid production of thrombin. However, excess production of thrombin by inflammatory reaction in damaged blood vessels causes thrombosis, which impairs the function of essential organs. Thrombin inhibitors such as heparin and warfarin, which inhibit thrombin production or directly block thrombin activity, have long been used as anticoagulants to treat or prevent thrombosis. Currently, new anticoagulants are being sought that exhibit a more reliable dose-dependent medicament effect, and which are safer and suitable for oral administration.
The blood clotting mechanism has been classified into two pathways, the “intrinsic clotting pathway” which begins with activation of factor XII (FXII) upon contact with negatively charged substances, and the “extrinsic clotting pathway” which is activated by tissue factor (TF) and factor VII (FVII), and since the pathology of thrombosis onset is associated with specific expression of TF, it has been suggested that extrinsic clotting is of major importance. Compounds that inhibit clotting factor VIIa, which is furthest upstream in the extrinsic clotting pathway of the clotting cascade, are thought to have potential use as therapeutic and/or prophylactic agents for diseases associated with thrombus formation, such as thrombosis, in which the extrinsic clotting mechanism plays a part.
As compounds that inhibit clotting factor VIIa there are known in the prior art amidinonaphthol derivatives (see Non-patent document 1), amidino derivatives (see Patent document 1), N-sulfonyldipeptide derivatives (see Patent document 2), 6-[[(allyl)oxy]methyl]naphthalene-2-carboxyimidamide derivatives (see Patent document 3) and phenylglycine derivatives (Patent documents 4 and 5).
However, these known compounds have still been inadequate from the standpoint of inhibiting activity against clotting factor VIIa, blood clotting effects and thrombosis-treating effects.    [Non-patent document 1] Tetrahedron, 55, p. 6219, 1999    [Patent document 1] EP 1078917    [Patent document 2] WO 00/58346    [Patent document 3] WO 00/66545    [Patent document 4] WO 00/35858    [Patent document 5] WO 00/41531